Hypomelanosis of Ito [incontinentia pigmenti achromians]

Are You Confident of the Diagnosis?

What you should be alert for in the history

Hypomelanosis of Ito [incontinentia pigmenti achromians] (HMI) is not one diagnosis, but a descriptive term for patterned pigmentary changes of the skin associated with underlying genetic mosaicism and, frequently, systemic abnormalities beyond the skin. The mosaicism may be at the chromosomal, single gene, or epigenetic levels, including pigmentary patterning that correlates with X-inactivation in females.

Skin changes are usually noted at, or very shortly after, birth. Localized or more systematized streaks, patches, or swirled patterns of color change are present without preceding eruption or inflammation. Usually the patterned areas are lighter in color than the surrounding skin, being hypopigmented, rather than depigmented, but the light versus dark pattern may also be reversed. Sometimes the dominant skin color is difficult to determine.

Since surrounding “normal” skin typically darkens with age, the hypopigmented lesions of HMI may become more noticeable over time, but generally do not change dramatically once they appear. The patterned skin cgureshanges may be seen in a child with other physical variations and/or developmental/neurologic concerns.

Characteristic findings on physical examination

Classically, HMI is characterized by patterned hypopigmentation in streaks, patches and whorls. The patterning may be found on virtually any part of the body, often following the “lines of Blaschko” on the trunk and extremities (Figures 1, 3, 5). The lines of Blaschko are thought to represent ectodermal migration patterns of keratinocytes and melanocytes during embryogenesis; on the trunk, the lines are wavy and swirled, with more linear patterns on the extremities.

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Other mosaic skin patterns include the “checkerboard” pattern and the “phylloid” pattern which may be associated particularly with duplications of chromosome 13. Localized hypopigmentation may also affect body and scalp hair. Skin changes of HMI are frequently associated with asymmetric somatic growth (hemihyperplasia), other variant physical features, and systemic malformations and neurologic abnormalities, with the presentation depending on the distribution of genetic variation or imbalance in individual groups of somatic cells.

Estimates of the frequency of extracutaneous manifestations associated with HMI range from 30-90%. The recognition of HMI warrants a thorough physical and neurologic evaluation of the affected child for other possible problems. A more localized distribution of patterned hypopigmentation may or may not be associated with other abnormalities; this can be referred to as “nevus depigmentosis.”

Expected results of diagnostic studies

Management and prognosis in HMI depends on the precise genetic diagnosis and the extent of the mosaicism. Both are sometimes difficult to fully assess, but the nature of the defect may directly impact management and prognosis, as well as genetic counseling. Therefore, every effort should be made to identify the genetic basis of each case of HMI unless the distribution of pigmentary mosaicism is very limited and growth and development seem entirely normal. In addition, other clinical screening including potentially costly imaging studies, may also be appropriate.

Cytogenetic analysis in HMI may reveal mosaicism for numerical or structural chromosome variations, the most common underlying mechanism for patterned pigmentation. Abnormalities are more often detected in cultured fibroblasts from affected areas of skin than in peripheral blood, but blood may be analyzed first. This test should include a request for extra cell counts to increase the chance of detecting low-level mosaicism (Figure 2, Figure 4).

Because metaphases of cultured cells may show clonal “selection” for healthier, cytogenetically normal cells, if a particular chromosome anomaly is suspected clinically (eg, mosaic tetrasomy 12p described below) interphase analysis using a chromosome-specific, fluorescently tagged DNA probe-fluorescence in situ hybridization (FISH) can be utilized with less bias and an increase in the number of countable cells. Chromosome microrarray analysis (CMA)/comparative genomic hybridization (CGH) is another testing option that greatly increases the chance of finding abnormal dosage involving very small chromosome segments, but the technique variably increases or decreases the likelihood of detecting low level mosaicism.

Cytogenetic and molecular cytogenetic studies may be initiated in peripheral blood leukocytes of patients with HMI. However, peripheral blood analysis frequently does not detect a cytogenetic change if the mosaicism is confined and/or the cytogenetically aneuploid cells are less stable in cell culture.

Ultimately, a skin biopsy or biopsies may be necessary for diagnosis. Biopsies should be submitted for several diagnostic tests, including histologic as well as cytogenetic studies. Part of the biopsy should be placed in sterile cell growth medium to establish a fibroblast cell culture for cytogenetic studies. Either one or two samples should be obtained, so that skin from both light and dark areas is sampled. If only one biopsy is obtained, it should be taken from a border zone between light and dark skin. Typically, at least a 4 mm punch biopsy is needed.

Reasons for failure to detect chromosome mosaicism can include sampling error, with an insufficient number of cells studied, a very low-level of mosaicism with instability of aneuploid cells in culture, mosaicism which is present only in melanocytes or keratinocytes, but not in lymphocytes or fibroblasts, mosaicism which is limited to a single gene mutation, below the level of resolution of cytogenetic studies or CMA, or localized epigenetic changes that influence gene expression, but not dosage.

Mosaicism may involve virtually any chromosome, in part or in full. Mosaicism for sex chromosome anomalies and X;autosome translocations are not uncommon, with pigmentary patterning also influenced by local patterns of X-inactivation in females (“lyonization”) (Figure 3, Figure 4). Mosaicism for mutations in single genes that affect pigmentation can also underlie HMI. Mosaic triploidy (69 chromosomes) and tetraploidy (92 chromosomes) can also be seen with HMI (Figure 5); these disorders are associated with very extensive phenotypic variations and severe neurologic involvement.

Mosaicism for tetrasomy 12p is a recognizable clinical syndrome associated with HMI: the Pallister-Killian syndrome. Pallister-Killian syndrome is most often associated with severe mental retardation, characteristic craniofacial features (sparse anterior scalp hair, flat occiput, hypertelorism, short nose/anteverted nostrils, flat nasal bridge, and short neck), severe congenital anomalies and high infant mortality (Figure 6, Figure 7). streaky pigmentation of the neck in a young girl with an unusually mild form of Pallister-Killian syndrome, presumably because the number and distribution of cytogenetically abnormal cells is more restricted .

Figure 6.

Figure 7.

The chromosome abnormality is virtually never detectable in metaphase karyotypes of cultured peripheral white blood cells, but is more likely to be found in cultured skin fibroblasts, which is how the diagnosis is usually established. CMA/CGH and interphase FISH have recently been shown to reliably detect the mosaicism even in peripheral blood samples, potentially circumventing the need for a relatively more invasive skin biopsy.

Histologic findings in HMI itself are likely to be nonspecific, with normal-appearing melanocytes, but the biopsy can distinguish HMI from neurocristopathies with a paucity of melanocytes (e.g., piebaldism, Waardenburg syndrome), pigment incontinence (eg, incontinentia pigmenti), and acquired melanocytic pathology (eg, vitiligo). Since early stage epidermal nevi are typically macular, the biopsy can also easily exclude this type of lesion in the differential diagnosis. A biopsy should be examined microscopically by routine histologic methods and potentially, by staining for melanocytic markers.

In addition to histologic studies, part of the biopsy should be set aside in sterile culture medium for establishing a fibroblast culture for cytogenetic and molecular studies. At least 50 cells from each section of skin, light and dark, should be studied to effectively screen for low level mosaicism. The sample could also be used to extract DNA directly for chromosome microarray analysis. However, sometimes only the more genetically “normal” cells are reflected in this analysis. Cytogenetic evaluation of keratinocytes is another consideration.

Diagnosis confirmation

Since it may be difficult to distinguish whether the pathologic lesion represents hypopigmentation on a darker background or hyperpigmentation on a lighter background, the differential diagnosis is broad, including piebaldism, vitiligo, Waardenburg syndrome, early stage epidermal nevi, and X-linked dominant incontinentia pigmenti (IP).

IP is due to a mutation, often an intragenic deletion of exons 4-10, in the NEMO (IKBKG) gene. In this X-linked dominant disorder, typically observed in females only because of male lethality (except in those with 47,XXY karyotypes) there is commonly a progression of cutaneous changes in stages beginning in the newborn period, with vesicles, followed by verrucous lesions, then patterned hyperpigmentation in streaks and whorls along the lines of Blaschko (see Figure 8).

Figure 8.

Frequently, there is a fourth stage consisting of patterned hypopigmentation, alopecia, and/or cutaneous atrophy. Here, the patterning is thought to be related to localized differences in the X-inactivation pattern in affected females, with evolving cutaneous changes and the earlier inflammatory stages reflecting apoptosis of mutant cells, leading to “normalization” of the skin. This probably reflects selection against cells in which the X chromosome that carries the gene mutation is the active X within a given cell (selection against cells that have the “wrong” X turned on).

The mechanism of patterning is a “functional” form of genetic mosaicism based on the localized pattern of X-inactivation (“lyonization”) in females. IP may also be associated with other ectodermal abnormalities involving the hair, nails, and teeth, progressive retinopathy and, in some patients, neurologic abnormalities. (Figure 9).

Figure 9.

IP can be distinguished from HMI by histology that shows pigment incontinence and eosinophilic infiltrates in earlier vesicular lesions. Addtionally, gene analysis can be used to verify the most common mutation, an intragenic gene deletion, in most cases. IP would be less likely to be found in a boy unless there is an associated 47,XXY karyotype. Interestingly, less deleterious mutations in the same gene may cause a somewhat different phenotype in 46,XY boys who have ectodermal dysplasia and immunodeficiency (MIM # 300291); these mutations are associated with a more traditional X-linked pattern of inheritance.

Early stage epidermal nevi are typically macular and clinically show light brown pigmentation with patterning. Histology would readily distinguish a nevus from HMI.

Nevus depigmentosus is a more localized form of patterned hypopigmentation, with lesions that are much more restricted in distribution and are not associated with other systemic abnormalities. It is possible that nevus depigmentosus represents a very restricted form of mosaicism. A similar underlying mosaic mechanism may underlie “linear and whorled hypermelanosis.”

Piebaldism and vitiligo would be associated with a paucity of melanocytes histologically and in the case of vitiligo, possibly inflammation in early stages. Vitiligo lesions also change their appearance over time. Piebaldism and depigmented patches are associated with mutations in the KIT and the Waardenburg syndrome family of genes (PAX3, MITF, SOX10, EDNRB, EDN3).

Who is at Risk for Developing this Disease?

HMI may be seen in individuals of any race and in both sexes. There are no known predisposing or pregnancy-related factors. Recurrence risks are low in most cases, but if genetic mosaicism is present within the gametes of an affected individual, there is potential to transmit the genetic aberration in non-mosaic form to offspring, potentially with more serious and often lethal consequences.

What is the Cause of the Disease?

Etiology

The cause of HMI in many cases can be proven to be postzygotically-acquired mosaicism for a chromosome or chromosomal segment, mosaic dosage of, or mosaicism for a point mutation within a single autosomal gene that affects pigmentation. It may also be due to random X-inactivation associated with certain X-linked disorders. A general mechanism is shown in Figure 9. The earlier the chromosome change or genetic variation develops, the greater the proportion of somatic cells that are affected.

In HMI due to chromosome mosaicism, the most common mechanism, any chromosome or chromosome segment may be involved, accounting for the wide variability in manifestations. Autosomal and sex chromosome translocations, deletions, duplications/trisomies, and mosaic triploidy/tetraploidy are all possible etiologies of HMI.

In certain balanced translocations between the X-chromosome and an autosome, functional segmental disomy of the X has also been implicated in HMI. I have also personally observed a case of HMI and Wilms tumor associated with an imprinting abnormality of the H19 gene within the Beckwith-Wiedemann syndrome locus on chromosome 11p15.

Pathophysiology

The extent of the skin lesions and severity of the systemic manifestations depends on the proportion of cells carrying the genetic change vs normal cells, and their distribution. In addition to an underlying mosaic chromosome change or single gene mutation, there is also the possibility of an acquired, secondary postzygotic mutation, such as loss of heterozygosity or other epigenetic changes.

Systemic Implications and Complications

Skin changes may be associated with poor growth, accelerated growth, or asymmetric somatic growth (hemihyperplasia), other variant facial and external physical features, and internal anatomic and neurologic abnormalities, with the pattern depending on the distribution of genetic imbalance in somatic cells. The recognition of HMI warrants a thorough physical and neurologic evaluation of the affected child for other potential problems.

Leg length discrepancy is not uncommon with HMI and could be treated with a simple lift in the shoe of the shorter leg. Stringent photoprotection for hypopigmented areas of skin is also warranted.

Occasionally, a recognizable phenotype such as Pallister-Killian syndrome or mosaic Turner syndrome may be suggested from the physical examination itself.

Treatment Options

Treatment is directed to individual non-cutaneous aspects of the phenotype that might be amenable to therapy, focused on problems that most directly impact overall physical and mental health. Examples include treatment of a seizure disorder, referral of a child to early intervention and educational support services if there is developmental delay, correcting a leg-length discrepancy to aid in ambulation, surgical correction of a structural cardiac defect, among others.

Certainly, genetic counseling should also be provided, diagnostic approaches suggested and implemented, management and counseling ultimately targeted to the specific chromosome or genetic change if this can be identified.

Stringent photoprotection of the lighter skin areas is strongly recommended. The skin pigmentation could be made more homogeneous if desired in older children and adults through cosmetic approaches with the application of makeup to darken lighter areas, or pharmacologic “bleaching” of the darker areas of skin.

Optimal Therapeutic Approach for this Disease

The optimal treatment approach is determined entirely by the needs of the patient, which reflect the specific genetic abnormality and its mosaic distribution among the various tissues and organs of the body. Certain forms of HMI may be associated with very high fetal or infant mortality or a poor long-term prognosis. Other cases may be fairly benign. The key to optimizing management is defining as much as possible the extent of the associated abnormalities as soon as HMI is recognized in the cutaneous exam.

It is also important to try to define the underlying genetic basis of HMI if at all possible, as this knowledge may direct further management. For example mosaic forms of Turner syndrome or other X-chromosome anomalies warrant cardiology evaluation including screening for coarctation of the aorta, treatment of growth and endocrinologic issues, and renal ultrasound to screen for structural anomalies.

Genetic counseling should be offered. In cases where an affected individual is entering the reproductive years, a review and possible re-evaluation of the underlying genetic basis should be undertaken. Pre-implanation or prenatal diagnosis can be offered to screen for chromosomal aneuploidy, most likely in non-mosaic form, in the offspring of such an individual.

Treatment in general is aimed at individual aspects of the frequently multisystemic involvement rather than the HMI itself. HMI cannot be cured, as the mosaicism determined developmental patterning early in fetal life.

With respect to the skin itself, stringent photoprotection of the lighter skin areas is strongly recommended. The skin pigmentation could be made more homogeneous if desired in older children and adults through cosmetic approaches with the application of makeup to darken lighter areas, or pharmacologic “bleaching” of the darker areas of skin utilizing hydroquinones.

Patient Management

A typical work-up might include a detailed clinical genetics/dysmorphology-based examination, detailed genetic and histologic studies, and depending on symptoms, CNS imaging (eg, brain MRI), selected X-rays, complete ophthalmologic/funduscopic examination, audiology, echocardiogram, ultrasound examinations of the viscera (liver, spleen, kidneys, pelvis), general laboratory screens (CBC, chemistries, urinalysis), and other subspecialty consultations as indicated by the other evaluations.

Treatment must be individualized, tailored to the specific problems identified, eg, management of seizures or congenital heart disease. Occasionally, a recognizable phenotype such as Pallister-Killian syndrome or mosaic Turner syndrome may be suggested from the physical examination itself.

Genetics re-evaluation every 6-12 months is useful during the first few years of life. This can be helpful in assessing growth patterns and screening for hemihyperplasia, as well as malformations and developmental delay that may not be apparent earlier in infancy. Standard of care guidelines for medical management of selected chromosomal disorders such as Turner syndrome have been published and can also be applied to mosaic cases. Other follow-up will be dictated by the nature of HMI-associated physical and neurologic abnormalities. Clinical genetics re-evaluation and counseling should be offered again during adolescence and prior to an anticipated pregnancy if a prospective parent is affected with HMI and genetic mosaicism.

Unusual Clinical Scenarios to Consider in Patient Management

Management and prognosis in HMI depends on the precise genetic diagnosis and the extent of the mosaicism. Both are sometimes difficult to fully assess, but the nature of the defect may directly impact management and prognosis, as well as genetic counseling. Therefore, every effort should be made to identify the genetic basis of each case of HMI unless the distribution of pigmentary mosaicism is very limited and growth and development seem entirely normal. In addition, other clinical screening, including potentially costly imaging studies, may also be appropriate.

In addition to the assessment of metaphase chromosomes in leukocytes, other options include interphase FISH analysis of clinically-suspected chromosome aberrations (eg, sex chromosome anomalies, Pallister-Killian syndrome), chromosome microarray analysis/comparative genomic hybridization to detect very small segmental anomalies and/or cytogenetic and molecular studies in cultured fibroblasts and/or keratoinocytes from light and dark areas of skin. Other genetic loci known to be subject to imprinting/methylation changes may also be candidates for genetic study.

What is the Evidence?

Sybert, VP, Pagon, RA, Donlan, M, Bradley, CM. “Pigmentary abnormalities and mosaicism for chromosomal aberration: association with clinical features similar to hypomelanosis of Ito”. J Pediatr. vol. 116. 1990. pp. 581-86. (This is a seminal article linking the cutaneous phenotype of HMI to chromosome mosaicism.)

Sybert, VP. “Hypomelanosis of Ito: a description, not a diagnosis”. J Invest Dermatol. vol. 103. 1994. pp. 141S-143S. (Description of hypomelanosis of Ito.)

Taibjee, SM, Bennett, DC, Moss, C. “Abnormal pigmentation in hypomelanosis of Ito and pigmentary mosaicism: the role of pigmentary genes”. Brit J Dermatol. vol. 151. 2004. pp. 269-82. (The authors reviewed published cytogenetic abnormalities associated with pigmentary mosaicism. They identified multiple cases that involved mosaicism for dosage of specific pigmentation genes such as the P gene on chromosome 15q11.2. They also noted several cases of mosaicism for genes involved in neural crest cell differentiation, with the “HMI” phenotype associated in such cases with complete depigmentation, rather than hypopigmentation, in a Blaschkoid pattern.)

Itin, P, Burger, B. “Mosaic manifestations of monogenic skin diseases”. JDDG. vol. 7. 2009. pp. 744-8. (The authors review the varieties of mosaic skin patterns and the underlying genetic mechanisms.)

Treat, J. “Patterned pigmentation in children”. Pediatr Clin N Am. vol. 57. 2010. pp. 1121-9. (The author provides a thorough overview of several disorders of patterned pigmentation, including HMI, from a clinical, cutaneous perspective.)

Sun, BK, Tsao, H. “X-chromosome inactivation and skin disease”. J Invest Dermatol. 2008. pp. 2753-9. (This is an excellent review of the process of X-inactivation as well as autosomal imprinting as it relates to skin pigmentary patterning.)

Rivera, H, Correa-Cerro, LS, Robinson, DO, Crolla, JA. “Functional Xp disomy and hypomelanosis of Ito”. Arch Med Res. vol. 31. 2000. pp. 88-92. (These authors studied site-specific X-inactivation of the androgen receptor locus in a girl with HMI, psychomotor retardation and seizures who had a balanced de novo X-autosome translocation [46,X,t(X;13)(q11;p10)]. The X-inactivation center on proximal Xq was not disrupted by the translocation. In normal skin, there was skewed X-inactivation favoring the translocated X. However in DNA extracted from hypopigmented skin, both the normal and translocated X were active, resulting in functional disomy for Xp. These observations support the theory that mosaic functional Xp disomy may underlie HMI.)

Taibjee, AM, Hall, D, Balderson, D, Larkins S Stubbs, T, Moss, C. “Keratinocyte cytogenetics in 10 patients with pigmentary mosacism: identification of one case of trisomy 20 mosaicism confined to keratinocytes”. Clin Exper Dermatol. vol. 34. 2009. pp. 823-9. (The authors suggested that analysis of keratinocytes may be more sensitive than skin fibroblasts in identifying cytogenetic mosaicism in patients with pigmentary mosaicism.)

Treff, NR, Levy, B, Su, J, Northrop, LE, Tao, X, Scott, RT. “SNP microarray-based 24 chromosome aneuploidy screening is significantly more consistent than FISH”. Mol Hum Reprod. vol. 16. 2010. pp. 583-9. (In this study, microarray detected mosaicism less frequently than FISH, but SNP microarray gave more complete and consistent results than FISH.)

Theisen, A, Rosenfeld, JA, Farrell, SA. “aCGH detects partial tetrasomy of 12p in blood from Pallister-Killian syndrome cases without invasive skin biopsy”. Am J Med Genet. vol. 149A. 2009 May. pp. 914-8. (Tetrasomy 12p was detectable using comparative genomic hybridization and interphase FISH in peripheral blood leukocytes in seven patients with Pallister-Killian syndrome, in contrast to conventional metaphase cytogenetic analyses of peripheral blood which were negative in all but one patient.)

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